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*
Department of Nephrology, Leiden University Medical Center, Leiden, The
Netherlands.
Department of Immunohematology and Blood Bank, Leiden University Medical
Center, Leiden, The Netherlands.
Correspondence to Dr. Cees van Kooten, Department of Nephrology, Leiden University Medical Center, Building 1, C3P, Albinusdreef 2, 2333 ZA Leiden, The Netherlands. Phone: 31 71 526 3964; Fax: 31 71 524 8118; E-mail: Kooten{at}LUMC.nl
Abstract. Renal allograft rejection is characterized by an influx
of inflammatory cells. Interaction between infiltrating T cells and resident
parenchymal cells might play an important role in the ongoing inflammatory
response. The present study demonstrates that CD40L, a product of activated T
cells, is locally expressed in kidneys undergoing rejection. Furthermore,
during rejection, CD40 expression not only is present on most graft
infiltrating cells but also is increased on resident tubular epithelial cells
(TEC). To obtain more detailed insight in the consequences of T cell/TEC
interaction, we analyzed the production of chemokines, including interleukin-8
(IL-8), monocyte chemoattractant protein-1 (MCP-1) and regulated upon
activation, normal T cell expressed and secreted (RANTES), and the production
of IL-6 by cultured human primary TEC in response to activation with CD40L
in vitro. In addition, we studied the interaction with IL-17, a
T-cellspecific cytokine previously demonstrated to be present during
renal allograft rejection. The results, obtained by enzyme-linked
immunosorbent assay, indicate that simultaneous activation of TEC with IL-17
and CD40L synergistically enhances production of IL-6 (2.1-fold higher than
sum of single stimulations) and the chemokines IL-8 (15-fold) and RANTES
(5.8-fold) as demonstrated by statistical analysis (P < 0.05),
whereas effects on MCP-1 (1.4-fold) are additive. Part of the synergy can be
explained by increased CD40 expression on TEC upon IL-17 stimulation. The
synergy is not unique for TEC, because similar responses were found with human
synoviocytes and a foreskin fibroblast cell line (FS4). Stimulation of TEC
with CD40L results in activation of NF-
B and induction of cytokine
production by IL-17 and CD40L is prevented by addition of the NF-
B
inhibitor pyrrolidine dithiocarbamate. These data suggest an important role
for T cells in renal allograft rejection by acting on parenchymal cells via
both soluble mediators and direct cellular contact.
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